Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours

• Published in: Cancer chemotherapy and pharmacology Vol. 71; no. 2; pp. 543 - 549
• Main Authors: Lassen, U., Miller, W. H., Hotte, S., Evans, T. R. J., Kollmansberger, C., Adamson, D., Nielsen, D. L., Spicer, J., Chen, E., Meyer, T., Brown, K., Rafi, R., Sawyer, M. B.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.02.2013; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic agents; Area Under Curve; Biological and medical sciences; Cancer Research; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Ketoconazole - adverse effects; Ketoconazole - pharmacology; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - metabolism; Oncology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Quinazolines - pharmacokinetics; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Rifampin - pharmacology; Short Communication; Tumors; Young Adult; Rifampicin; Advanced solid tumours; Ketoconazole; CYP3A4; Pharmacokinetics; Cediranib; Human; Imidazole derivatives; Evaluation; Solid tumor; Cytochrome CYP3A4; Enzyme; Isozyme; Cytochrome P450; Malignant tumor; Advanced stage; Protein synthesis inhibitor; Antiangiogenic agent; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-2038-0

Purpose To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours. Methods In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib. Results In the ketoconazole study, 46 patients were dosed; 38 were evaluable for C ss,max , 36 for AUC ss . gMean AUC ss and C ss,max for cediranib 20 mg increased by 21 % (94 % CI 9–35 %) and 26 % (94 % CI 10–43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C ss,max and 41 for AUC ss . gMean AUC ss and C ss,max for cediranib 45 mg decreased by 39 % (90 % CI 34–43 %) and 23 % (90 % CI 16–30 %), respectively, in the presence of rifampicin. gMean ratios for AUC ss and C ss,max were >1 for ketoconazole and <1 for rifampicin and CIs were outside the pre-specified equivalence boundaries, indicating a statistically significant effect. Significant inter-patient variability in cediranib AUC ss and C ss,max was observed. The safety profile of cediranib was similar to that reported previously. Conclusions Co-administration of ketoconazole or rifampicin had statistically significant effects on steady-state pharmacokinetics of cediranib in patients with advanced solid tumours. Therefore, caution is advised when administering cediranib with potent enzyme inhibitors or inducers.